tbuckley/cabot-search huggingface dataset:
A phase Ib/II study of AK112, a PD-1/VEGF bispecific antibody, as first- or second-line therapy for advanced non–small cell lung cancer (NSCLC).
Authors: Caicun Zhou, Shengxiang Ren, Yongzhong Luo, Lei Wang, Anwen Xiong, Chunxia Su, Zhihong Zhang, Wei Li, Jin Zhou, Xinmin Yu, Yanping Hu, Xiaodong Zhang, Xiaorong Dong, Xiaoming Hou, Yuanrong Dai, Weifeng Song, Baiyong Li, Zhongmin Maxwell Wang, Yu Xia
Journal: Journal of Clinical Oncology (2022)

9040 Background: Besides the well-known antiangiogenic effects, anti-VEGF agents also modulate the tumor immune micro-environment, leading to synergic anti-tumor effects. AK112 is a humanized IgG1 bispecific antibody against PD-1 and VEGF. Here, we reported results of an ongoing phase Ib/II trial of AK112 in advanced NSCLC pts. Methods: Pts with stage IIIB/IIIC/IV NSCLC, ECOG PS 0-1 and negative oncogenic drivers were enrolled and given AK112 (10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W or 30 mg/kg Q3W) intravenously. The primary endpoints were ORR per RECIST v1.1 and safety. Results: At data cutoff (January 5, 2022), 94 pts were enrolled: median age 66.0 years (range: 48-75), PS 1 90.4%, male 85.1%, non-squamous 48.9%, PD-L1 positive (TPS ≥1%) 70.2% and treatment-naïve 84.0%. Of 83 pts evaluable for efficacy, ORR (unconfirmed, similarly hereinafter) and DCR were 22.2%/88.9%, 44.0%/92.0%, 37.9%/93.1% and 100%/100% at doses of 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W and 30 mg/kg Q3W, respectively. When doses of AK112 &gt; 10mg/kg Q3W, ORR and DCR were 42.9% (24/56) and 92.9% (52/56) in 56 evaluable pts, 56.3% (18/32) and 100% (32/32) in pts with TPS≥1% at 1 st line setting, and 23.5% (4/17) and 76.5% (13/17) in pts with PD-L1 TPS &lt; 1%, respectively. Grade≥3 treatment-related adverse events (TRAEs) occurred in 10.6% (10/94) pts, in which the most common event (occurring in &gt; 1 pt) was pneumonia (2.1%, 2/94). No TRAEs led to permanent treatment discontinuation. Most frequent TRAEs (incidence ≥10%) were proteinuria (17.0%), hypertension (16.0%), lipase increase (12.8%), alanine aminotransferase increase (12.8%), blood urea increase (10.6%), apolipoprotein E increase (10.6%) and hyperglycaemia (10.6%). No significant difference in the incidences of TRAEs were observed between non-squamous and squamous pts. Conclusions: In advanced NSCLC, AK112 was well-tolerated and presented remarkable anti-tumor efficacy. Further phase III studies are planned to validate the findings of this study. Clinical trial information: NCT04900363.
Survival outcomes for dostarlimab and real-world (RW) treatment (tx) paradigms in post-platinum patients (pts) with advanced/recurrent (A/R) endometrial cancer (EC): The GARNET trial versus an external control arm from the Flatiron Health database.
Authors: Robert L. Coleman, Qin Shen, Scott Goulden, Cara Amanda Mathews, Matthias Hunger, Ankit Pahwa, Rene Schade
Journal: Journal of Clinical Oncology (2022)

5593 Background: There are limited treatment options for pts with A/R EC progressing on or after platinum-based chemotherapy (PBCT) and their prognosis is poor. This study compared the efficacy of the anti-programmed death (PD)-1 antibody dostarlimab evaluated in the single-arm, Phase I GARNET trial with current RW tx. Overall survival (OS) of pts with A/R mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) EC receiving dostarlimab in Cohort A1 of the GARNET trial was compared with an equivalent RW cohort receiving non-anti-PD-(ligand [L])1 tx. Methods: The dostarlimab arm was the GARNET (Cohort A1) dMMR/MSI-H EC safety population. For the external control arm, a RW cohort was constructed using the Flatiron Health database and aligning eligibility criteria with those for GARNET, including pts with A/R EC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1, who had received ≤2 lines of chemotherapy (≥1 line PBCT) and no anti-PD-(L)1 therapy. GARNET pts who received anti-PD-(L)1 therapy following dostarlimab (n=5/129) were excluded. Inverse probability of tx weighting (IPTW) was performed based on propensity scores constructed from key prognostic factors identified by literature review and clinical experts. With IPTW, Kaplan–Meier curves were created, OS rates estimated, and adjusted hazard ratios (HR) estimated by a Cox regression model. MMR/MSI status, only partially available in Flatiron and considered not significantly prognostic for OS as per a recent meta-analyses, was not included in the IPTW. Results: Baseline characteristics for GARNET (N=124) and RW (N=185) after IPTW are shown in the Table. Dostarlimab was associated with a 44% lower risk of death compared with RW tx (OS HR [95% confidence interval {CI}] 0.56 [0.385–0.812]; p=0.002) (see Tablefor median OS). Survival rates (95% CI) were higher for dostarlimab than RW tx at 12 months (mos) (72% [57%–82%] vs 51% [43%–59%]), 18 mos (57% [41%–70%] vs 40% [32%–48%]), and 24 mos (53% [37%–67%] vs 34% [26%–42%]). Conclusions: These results indicate that pts with A/R EC receiving dostarlimab in the GARNET trial had significantly lower risk of death than those receiving current non-anti-PD-(L)1 tx in the RW.[Table: see text]
Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Biomarker (BM) analyses by next-generation sequencing (NGS) from the SOLAR-1 study.
Authors: Dejan Juric, Hope S. Rugo, Albert Reising, Chong Ma, Eva M. Ciruelos, Sibylle Loibl, Christian F. Singer, Joohyuk Sohn, Mario Campone, Pierfranco Conte, Hiroji Iwata, Farhat Ghaznawi, Michelle Kristine Miller, Tetiana Taran, Fei Su, Fabrice Andre
Journal: Journal of Clinical Oncology (2022)

1006 Background: PIK3CA mutations (mut; ~40% of HR+, HER2– ABC) are linked to poor prognosis. In SOLAR-1, ALP (PI3Kα-selective inhibitor and degrader) + FUL improved progression-free survival (PFS) vs placebo (PBO) + FUL in pts with PIK3CA-mutated HR+, HER2– ABC. Here, we focus on efficacy data by gene alterations in SOLAR-1 PIK3CA-altered (alt) cohort. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP (or PBO) + FUL in HR+, HER2– ABC progressing on/after an aromatase inhibitor. Baseline tissue samples with enough quantity/quality (N = 398) were retrospectively tested by NGS (FoundationOne CDx 324-gene panel) and pts grouped by PIK3CA-alteration status. Clinical benefit was assessed using PFS and hazard ratio (HR) based on tumor mutational burden (TMB) and gene alteration status in the PIK3CA-alt cohort. No multiplicity adjustment was made. Results: PIK3CA-alt (ALP, n = 120; PBO, n = 117) and PI3KCA-non-alt (ALP, n = 81; PBO, n = 80) cohorts had differential gene alteration landscapes. In the PIK3CA-alt cohort, ALP + FUL clinical benefit was seen across TMB quartiles (Q1: 0 -&lt;2.52, Q2: 2.52 -&lt;3.78, Q3: 3.78 -&lt;5.04, Q4: ≥ 5.04 mut/megabase). ALP + FUL had greater benefit in pts with alt vs non-alt FGFR1/ 2 (Table). ALP + FUL benefit was independent of alterations in TP53, ESR1, CCND1, MAP3K1, and ARID1A and limited in MYC- and RAD21-alt cohorts . ALP + FUL benefit was seen in pts with alt genes in the MAPK (HR [95% CI] vs PBO: alt 0.43 [0.23 - 0.80]; non-alt 0.56 [0.40 - 0.79]) and PI3K (in addition to PIK3CA; alt 0.68 [0.38 - 1.23]; non-alt 0.48 [0.34 - 0.68]) pathways, and implicated in CDK4/6i resistance (alt 0.52 [0.30 - 0.89]; non-alt 0.53 [0.37 - 0.76]). Conclusions: The unique mut profile of PIK3CA-alt tumors did not affect ALP + FUL benefit in pts with HR+, HER2– ABC. Clinical benefit was maintained regardless of alterations in most BMs, including ESR1 and genes implicated in CDK4/6i resistance, consistent with ALP targeting the PIK3CA driver oncogene. Clinical trial information: NCT#02437318; EUDRA CT#2015-000340-42. [Table: see text]
In-vivo reprogramming macrophages and dendritic cells with Allocetra-OTS: Successful mono- and combination-antitumor therapy.
Authors: Dror Mevorach, Yehudit Shabat, Eshchar Regev, Eran Yalon, Netanel Karbian, Barak Reicher
Journal: Journal of Clinical Oncology (2022)

2532 Background: Chimeric antigen receptor (CAR) T cells can activate an immune response to a cancer-specific antigen but is less effective in solid tumors. Immune check point inhibitors (ICI) revolutionized the treatment of solid tumors, however, in many tumors only partial response is achieved. Here we questioned the role of synergistic effect of Allocetra-OTS (cellular therapy for in-vivo reprogramming macrophages and dendritic cells, Enlivex Therap.) on solid tumor progression. Methods: To follow tumor growth in vivo, HeLa-CD19 cells were stably transduced with pLenti-PGK-V5-Luc-Neo. For CAR preparation, fresh mononuclear cells (MNC) were transfected with CD19-CAR plasmids. For the intraperitoneal solid tumor model, SCID-Bg mice were injected intraperitoneally (IP) with human HeLa-CD19 or HeLa-CD19-luciferase cells, 10×10 6 allocetra-OTS or vehicle, and 10×10 6 CD19-CAR T cells or mock T cells. In an immune-competent model, Balb/c mice were treated IP with AB12 (mesothelioma) with pLenti-PGK-V5-Luc-Neo and treated with anti-CTLA4 with or without Allocetra-OTS. Mice were monitored daily for clinical signs and peritoneal fluid accumulation and weekly for tumor growth. Kaplan-Meier log rank test was done for survival. Peritoneal cells were evaluated using single cell analysis and flow cytometry. Tumors were examined for bacterial presence by immunohistochemistry staining with antilipoteichoic acid (LTA) and antilipopolysaccharide (LPS). For allocetra-OTS preparation, enriched mononuclear fractions were collected by leukapheresis from healthy eligible human donors and induced to undergo early apoptosis. Results: SCID mice survived 30±5 days (range 27–37) and were sacrificed or died from solid tumor in the peritoneal cavity after accumulation of bloody peritoneal fluid and clinical deterioration. Results were verified using IVIS of intraperitoneal HeLaCD19-Luc cells. CAR T cell therapy significantly ameliorated survival to 55±11 days (p &lt; 0.05 vs MOCK) but Alloctra-OTS further ameliorated survival to 75±10 (p &lt; 0.001) with 20-40% complete remission. In AB12 model, anti CTLA4 therapy significantly ameliorated survival from 26±5 to 38 ±9 days (p &lt; 0.05). However, Allocetra-OTS monotherapy ameliorated survival to 45 ±12 days (p &lt; 0.02) and combinational therapy to 75±9 days (p &lt; 0.0001) with complete remission in 60-75% of mice. Single cell analysis revealed that restoration of large peritoneal macrophages (LPM), were associated with antitumor activity. Conclusions: During intraperitoneal tumor progression, allocetra-OTS as monotherapy or combinational therapy with CAR or anti-CTLA4 significantly reduced tumor size and enable complete remission in up to 75% treated mice. Based on excellent safety profile in &gt; 30 patients treated for sepsis and Covid19, human phase I/II of allocetra-OTS plus ICI, for peritoneal metastases, is planned for 2022.
Prostate volume is associated with optimal TRIFECTA outcomes after HoLEP – results from a prospective trial (ExpHo)
Authors: P. Capogrosso, E. Ventimiglia, G. Fallara, A. Costa, M. De Angelis, G. Colandrea, F. Belladelli, F. Pellegrino, L. Candela, E. Pozzi, D. Cignoli, N. Schifano, W. Cazzaniga, R. Matloob, F. Dehò, V. Scattoni, A. Salonia, F. Montorsi
Journal: European Urology (2022)
Serum thymidine kinase 1 and its kinetics in HER2-positive breast cancer: Results from the Swedish phase II PREDIX HER2 trial.
Authors: Yajing Zhu, Kang Wang, Ioannis Zerdes, Alexios Matikas, Mattias Bergqvist, Ellinor Elinder, Ana Bosch, Henrik Lindman, Zakaria Einbeigi, Anne Andersson, Lena Carlsson, Ann Charlotte Dreifaldt, Erika Isaksson-Friman, Mats Hellstrom, Hemming Johansson, Jonas C. S. Bergh, Thomas Hatschek, Theodoros Foukakis
Journal: Journal of Clinical Oncology (2022)

e12598 Background: Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in HER2-negative early and metastatic breast cancer (BC). Here we present the first report of TK1 in HER2-postitive BC. Methods: In the PREDIX HER2 trial, 202 patients with HER2-positive BC were randomized to 6 cycles of neoadjuvant trastuzumab, pertuzumab and docetaxel or trastuzumab emtansine every three weeks followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum was prospectively collected from all participants at multiple timepoints: At baseline, after cycles 2, 4 and 6, at end of adjuvant therapy and then annually for 5 years and in case of recurrence. TK1 activity was measured by DiviTum assay (Biovica, Sweden), blinded to treatment allocation, patient characteristics and outcome. TK1 activity was correlated with baseline characteristics, pathologic complete response (pCR) and event-free survival (EFS). Results: Baseline TK1 activity as categorical variable was not associated with tumor size or hormone receptor expression. An increase of TK1 activity was seen in the majority of cases after treatment (mean TK1 at baseline = 111.7, after cycle 2 = 1257.0, after cycle 4 = 1157.0, after cycle 6 = 1178.0). Neither baseline TK1, on-treatment TK1 nor its change from baseline to cycle 2 were significantly associated with pCR in multivariable logistic regression analysis (Table). Baseline TK1 activity was not predictive for differential benefit to the study treatments ( p interaction = 0.19). After a median follow-up of 52.5 months, 21 patients had EFS events. There was no significant correlation between baseline TK1 activity and EFS in multivariable Cox regression analysis. Conclusions: Serum TK1 activity in HER2-positive BC increased following treatment with neoadjuvant therapy but was not correlated to pCR rates or EFS. [Table: see text]
Combination treatment of radiofrequency ablation and peptide neoantigen vaccination: Promising modality for future cancer immunotherapy.
Authors: Yong Fang, Jiawei Shou, Fan Mo, Shanshan Zhang, Lantian Lu, Ning Han, Liang Liu, Min Qiu, Hongsen Li, Weidong Han, Dongying Ma, Xiaojie Guo, Qianpeng Guo, Qinxue Huang, Xiaomeng Zhang, Shengli Ye, Hongming Pan, Shuqing Chen
Journal: Journal of Clinical Oncology (2022)

3151 Background: We previously reported the safety and immunogenicity of a personalized neoantigen-based peptide vaccine, iNeo-Vac-P01, in patients with a variety of cancer types. The current study investigated the synergistic effects between radiofrequency ablation (RFA) and neoantigen vaccination in cancer patients and tumor-bearing mice. Methods: 28 cancer patients were enrolled in this study, including 10 patients who had received RFA treatment within 6 months before scheduled for vaccination, and 18 patients who had not. Individualized neoantigen peptide vaccines were designed, manufactured, and delivered for all patients, followed by subcutaneous administration of GM-CSF as an adjuvant. Mouse models were used to validate the synergistic efficacy of combination treatment of RFA and neoantigen vaccination. Results: Longer median progression free survival (mPFS) and median overall survival (mOS) were observed in patients receiving RFA prior to vaccines compared to patients only receiving vaccines (4.42 and 20.18 months vs. 2.82 and 10.94 months). Ex vivo ELISpot assay showed that patients who received both had stronger IFN-γ responses against patient-specific neoantigens at baseline and post vaccination. Mice receiving RFA together with vaccine displayed higher antitumor immune responses than mice receiving single modality; addition of anti-PD-1 further enhanced the antitumor response. Conclusions: Neoantigen vaccination after RFA treatment led to an overall increase in clinical response and immune response among patients of different cancer types. Combination treatment of both modalities in mice further validated their synergistic antitumor potentials, which could be further enhanced by the addition of anti-PD-1. The mechanisms of their synergies require further investigation. Clinical trial information: NCT03662815.
Comparative effectiveness of trimodal therapy versus definitive chemoradiation in older adults with locally advanced esophageal cancer.
Authors: Charles Gaber, Nicholas J. Shaheen, Jessie K. Edwards, Robert S Sandler, Hazel Nichols, Hanna Kelly Sanoff, Jennifer Leigh Lund
Journal: Journal of Clinical Oncology (2022)

e16093 Background: The comparative effectiveness of trimodal therapy versus definitive chemoradiation for older adults with locally advanced esophageal cancer is uncertain. Only two randomized trials have considered this comparison, and older adults and patients with adenocarcinomas were underrepresented. Older adults have greater frailty and may not benefit from adding surgery to chemoradiation. Methods: A cohort of adults 66-79 years of age diagnosed with incident locally advanced esophageal cancer between 2004 and 2017 was identified using the Surveillance Epidemiology and End Results-Medicare database. We used observational data to emulate a hypothetical trial comparing trimodal therapy and definitive chemoradiation. Outcomes included overall mortality, esophageal cancer-specific mortality, functional adverse events, and healthy days at home. Results: The study population included 1,240 individuals with adenocarcinomas and 661 with squamous cell carcinomas. Amongst older adults diagnosed with adenocarcinomas, the five-year risk of mortality was 73.4% (95% CI: 69.1–77.4) in the trimodal therapy group and 83.8% (95% CI: 78.6–87.2) in the definitive chemoradiation group (RR= 0.88, 95% CI: 0.82–0.95). Amongst older adults diagnosed with squamous cell carcinomas, the five-year risk of mortality was 62.6% (95% CI: 50.9–73.5) in the trimodal therapy group and 72.3% (95% CI: 67.6–76.3) in the definitive chemoradiation group (RR= 0.87, 95% CI: 0.70–1.01). Results for all outcomes are presented in the Table. Conclusions: Trimodal therapy was associated with lower mortality than definitive chemoradiation. The benefits were smaller than suggested by prior observational studies. These findings can be used with clinical expertise and patient preferences to enhance shared decision-making. [Table: see text]
Transperineal interstitial laser ablation of the prostate as a minimally-invasive and effective therapeutic option for benign prostatic hyperplasia
Authors: C. Bebi, F. Ripa, M. Malfatto, G. Lucignani, M. Turetti, C. Silvani, L. Rocchin, M. Serrago, E. De Lorenzis, G. Albo, E. Montanari, L. Boeri
Journal: European Urology (2022)
Using customized PRO profiles to evaluate expected patient quality-of-life outcomes.
Authors: Charles Iaconangelo, Shauna McManus, Daniel Serrano
Journal: Journal of Clinical Oncology (2022)

e18607 Background: Patient Reported Outcomes (PROs) are routinely employed in patient-focused drug development programs. However, PRO data are often under-utilized. Better approaches could employ trial data to describe expected patient outcomes. The objective of this work was to present a method for leveraging PRO-based patient profiles to project and thereby anticipate expected patient outcomes. Methods: A model-based approach to analyzing PRO scores allows for a more tailored approach to evaluating outcomes of interest. To demonstrate this approach, we analyzed PRO data from a Phase 3 trial of patients with prostate cancer randomized to either Hypofractionated 3D-CRT/MRT (experimental arm) or Conventionally Fractionated 3D-CRT/MRT (comparator arm). The outcome of interest was the difference between treatment arms on the Expanded Prostate cancer Index Composite (EPIC) urinary domain scores, defined on the sum of responses to 12 items. A longitudinal regression model was fit to EPIC scores at 6, 12, 24, and 60 months post-baseline. Patient profile variables (baseline EPIC urinary scores, treatment arm, age, race, clinical T-stage, and Gleason score) were included as predictors. For a particular patient profile of interest, expected EPIC urinary score at 6 months was estimated, as well as associated 95% confidence intervals, which allowed for an understanding of the range of likely outcomes for that particular patient profile. Results: n = 550 patients in the experimental arm and n = 542 patients in the comparator were analyzed. The difference in EPIC urinary scores between treatment arms at 6 and 12 months were computed, with higher scores reflecting greater symptom severity. The model estimated a difference of 2.12 points (p = 0.009) at 6 months and 2.16 points (p = 0.013) at 12 months, favoring the experimental arm. To illustrate how customized patient profiles can be used to better understand patient outcomes, a single profile is presented. At baseline, a patient receiving the experimental treatment, EPIC urinary score 98.0, age 57, white, clinical T-stage T2, Gleason score 6, could be expected to report an EPIC urinary score of 94.3 (92.06, 96.00) at 6 months based on the statistical model. In the observed trial data, one patient with this profile reported an EPIC urinary score of 93.8 at 6 months. The expected EPIC urinary score overestimated the observed score by only 0.53%, indicating the accuracy of the expected EPIC urinary scores. This corresponds to approximately one category decrease on two of the 12 domain items (i.e., a decrease in symptom severity). Conclusions: Well-established statistical methods can lead to improved clinician understanding of expected outcomes specific to a given patient profile. This would facilitate communication between clinician and patient regarding anticipated oncology treatment outcomes. Recommendations to support the use of these methods should be considered.
Challenging the dogma: Should unilateral pelvic lymph node dissection be envisioned in the multiparametric prostate MRI era?
Authors: A. Martini, L. Wever, C.D. Fankhauser, J.B. Grogg, E. Checcucci, G. Ploussard, A. Affentrager, C. Kesch, T. Al-Hammouri, F. Zattoni, G. Marra, M. Apfelbeck, U.G. Falagario, O. Ettala, M. De Angelis, A. Briganti, I. Jambor, A. Kretschmer, V. Kasivisvanathan, T. Hermans, P.K. Chiu, R.C. Van Den Bergh, G. Gandaglia, M. Valerio
Journal: European Urology (2022)